3,7-disulfamyl-benzothiadiazine 1,1-dioxides



United States Patent C re 2,894,948 Patented July 14, 1959 3,7 -DISULFAMYL-BEN ZOTHIADIAZENE 1,1-DIOXIDES George De Stevens, New Providence,and Lincoln Harvey Werner, ummit, N.J., assignors to Ciba PharmaceuticalProducts, Inc., Summit, a corporation New Jersey No Drawing. ApplicationDecember 20, 1957 S rial No. 703,998 7 Claims. (Cl. 260-443) of suchcompounds. A halogen atom is more especially a fluorine or a bromine,particularly a chlorine atom; a

halogeno-methyl group is represented by a chl'oromethyl or primarily atrifiuoromethyl group. 7

Due to tautomerism the double bond of the 1,2,4-benzothiadiazine-1,1-dioxides nucleus may be accommodated in the 2,3- orin the 3,4-position', the compounds of the present invention may existin two forms of the formulae:

(\3-SO NHz NH HzhOzS \S/ and R p-sozNn. IIZNOzS- &

02 in which R has the above given meaning.

The new 1,2,4-benzothiadiazine derivatives of this invention havediuretic properties an may be used as diuretic agents, for example, inconditions causing excessive saltand water-retention, e.g. heartinsufiiciency, hypertension, liver damages or kidney diseases. The newcompounds may be used as medicaments in the form of pharmaceuticalpreparations, which contain the new compounds in admixture with apharmaceutical orcarrier suitable for ganic or inorganic, solid orliquid enteral or parenteral administration. For making up thepreparations there can be employed substances which do not react withthe new gelatine, lactose, starches, magnesium stearate, talc, vegetableoils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly orany other known carrier for medicaments. The pharmaceutical preparationsmay be in solid form, dragees, or in liquid form, isotonic solutions oremulsions. It may contain auxiliary substances, such as preservingagents, stabilizing agents, wetting or emulsifying agents, salts forvarying the osmotic pressure or buffers. They may also contain, incombination, other therapeutically useful substances, for example,hypotensive agents, rauwolfia alkaloids, such as reserpine,rescinnarnine l,2,4-benzothiadiazine-l,l-dioxides of this invention maybe prepared according to several methods. A particularly suitableprocedure comprises treating a solution of a3-mercapto-6-R-7-sulfamyl-l,2,4,-benzothiadiazine-l,l-dioxide, in whichR has the above given meaning, with a mixture of chlorine and oxygen,converting in the resulting product the sulfonyl chloride group into asuifamyl group by and isolating the desired6-R-3,7-disulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide.

The oxidation of the mercapto group of a 3-mercapto-6-R-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide may be carried out bytreatment of the starting material with chlorine in the presence ofoxygen, e.g. air with the simultaneous formation of a sulfonyl chloridegroup. This oxidation may be performed by bubbling a mixture of chlorineand air through a solution of the starting material, for example, inlower alkanoic acid, e.g. acid. The resulting sulfonyl chloridederivative is erably used without further purification.

The sulfonyl chloride group in the resulting 6-R-7- sulfamyl 1,2,4benzothiadiazine-l,l-dioxide-S-sulfonyl chloride is replaced by thesulfamyl group by treatment with ammonia, for example, liquid ammonia oraqueous ammonia. The desired6-R-3,7-disulfamyl-l,2,4-benzothiadiazine-Ll-dioxide may be isolated byremoving the ammonia, and is purified by recrystallization, for example,from a hydroxylated solvent, such as an alcohol, eJg. ethanol.

The 3-mercapto-6-R-7-sulfamyl-1,2,4-benzothiadiazine- 1,l-dioxides usedas the starting materials, which are new and are intended to be includedwithin the scope of this application, may be prepared, for examp e, byreplacing the oxo group in a 6-R-7-sulfamyl-l,2,4benzothiodiazine-3-one-l,l-dioxide, by a thiono group, which, by shifting of thetautomeric (1 bond, may be transformed into a mercapto group. Such areplacement may be carried out, by a6-R-7-sulfamyl-l,2,4-benzothiadiazine- 3-one-1,l-diox1de with phosphorustrisulfide or preferably with phosphorus pentasulfide, if desired, inthe presence of a solvent, such as a toluene, at an elevatedtemperature, boiling temperature of the solvent. The 6-R-7-sulfamyl-1,2,4-benzothiadiazine-3-one-l,l-dioxide may be obtained by reacting a5-R-2,4-disulfamyl-aniline with phosgene, preferably in a hydrocarbon,e.g. benzene or toluene, solution. Furthermore, the3-mercapto-6-R-7-sulfarnyl 1,2,4-benzothiadiaZine-1,l-dioxide used as astarting material may be prepared by treating 5-R-2,4-disulfamylaniline,in which R has the above given meaning, with thiophosgene to efiect thering closure to the 3-mercapto 1,2,4-thiadiazine-l,l-dioxide ring. Thethiophosgene is preferably added in a solution, for example, in ahydroprefcarbon, e.g. benzene or toluene, solution, to a solution of theaniline derivative in a similar solvent, e.g. benzene or toluene.

Example 1 A solution of 32.8 g. (0.1 mole) of 3-mercapto-6-chloro-7-sulfamyl-l,2,4-benzothiadiazine-l,l-dioxide in 300 ml. ofdilute acetic acid is treated with an excess of an air-chlorine mixtureby bubbling the gas through the stirred solution. he formed precipitateis collected without purification and added to liquid ammonia. Afterstirring for 2 hours the ammonia evaporate an the residue is taken up inwarm ethanol, from which the 6-chloro-3,7-disulfamyl-l,2,4-benzothia--diazine-l,l-dioxide precipitates upon cooling.

The 3-mercapto 6 chlor-7-sulfamyl-1,2,4-benzothia-- diazine-l,1-dioxideused as the starting material may be evaporated. The resulting3-mercapto-6-trifluorometh3 prepared as follows: To a solution of 85.6g. (0.3 mole) of 7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide is usedWil 5-chloro-2,4-disulfamyl-aniline in 500 m1. of toluene is out furtherpurification. 7

added a solution of 35 g. of thiophosgene in 100 ml. of What is claimedis:

toluene While stirring. The mixture is filtered, the filtrate 5 1. 6R-3,7 disulfamyl 1,2,4-benzothiadiazine-1,l-d. evaporated to drynessunder reduced pressure and the oxides, in Which R stands for a member ofthe grou; residue recrystallized from ethanol or a mixture of consistingof halogen and halogeno-methyl.

ethanol and Water to yield the desired 3-Inercapto-6- 2.'6-chloro-3,7-disulfamyl-l,2,4-benzothiadiazine-1,1chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide. dioxide.

10 3. G-trifiuoromethyl-3,7-disulfamyl-l,2,4-benzothiadia- Example 2zine-Ll-dioxide o gh a solution of 1805 g (005 mole) ofIi-mercapto--R-7-sulfamyl-1,2,4-benzothiadiazinecapto 6trifluoromethyl-7-sulfamyl-1,2,4-benzothiadiam Whlch R stands for amember of the group consisting of halogen and halogeno-methyl.3mercapto-6-chloro-7-sulfarnyl-1,2,4 benzothiadiastarting material, andthe resulting precipitate is filtered 011. It is immediately added to aconcentrated aqueous m f y y 3. 43611- ammonia solution, Which is heatedand stirred for 3 ZOthIadIaZme'LIdIOXIdehours and then concentratedunder reduced pressure. Process for the pfflipafatlon f- P -R-7- Theresidue is dissolved in Warm ethanol and the6-trisulfamyll24'benZth1ad1aZ1I1e-Ll-dloXlfiia 1H h h R fluoromethyl3,7-disulfamyl-l,2,4-benzothiadiazine-1,1- stands for a member offllegroup consisting of halogen di id lli upon cooling and halogeno-methylwhich comprises treating a 5-R-2,4-

e starting material used in the above reaction may disulfamyl-anilin inwhich R has the above given meanmg, with thiophosgene.

ene 15 added a solution of 20 g. of phosgene in 100 ml. References CitedIn the file of this Patent of toluene While cooling and stirring. Thesolvent is NITED STATES PATENTS stripped 01f, the residue, afterrcgcrystallization from 2,309,194 Noveuo Oct 8, 1957 ethanol, is takenup in 500 ml. of enzene and refluxed with 45 g. of phosphoruspentasulfide. The reaction OTHER REFERENCES mixture is filtered, Wateradded and the benzene solution Craig et al.: J. Org. Chem, vol. 22, p.7, June 1957. separated. The Water layer is extracted with benzene,Synthetic Org. Chem. (Wagner), N.Y., John Wiley the two benzene extractscombined, dried and the solvent (1953), pp. 821-822.

1. 6 - R-3,7 DISULFAMYL - 1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDES, IN WHICHR STANDS FOR A MEMBER OF THE GROUP CONSISTING OF HALOGEN ANDHALOGENO-METHYL. 4.3-MERCAPTO-6-R-7-SULFAMYL-1,2,4-BENZOTHIADIAZINE1,1-DIOXIDE, IN WHICH RSTANDS FOR A MEMBER OF THE GROUP CONSISTING OF HALOGEN ANDHALOGENO-METHYL.